Cardiomyocyte proliferation

Cardiomyocyte proliferation refers to the ability of cardiac muscle cells to progress through the cell cycle and continue to divide. Traditionally, cardiomyocytes were believed to have little to no ability to proliferate and regenerate after birth.[1] Although other types of cells, such as gastrointestinal epithelial cells, can proliferate and differentiate throughout life,[2] cardiac tissue contains little intrinsic ability to proliferate, as adult human cells arrest in the cell cycle.[3] However, a recent paradigm shift has occurred. Recent research has demonstrated that human cardiomyocytes do proliferate to a small extent for the first two decades of life.[4] Also, cardiomyocyte proliferation and regeneration has been demonstrated to occur in various neonatal mammals in response to injury in the first week of life.[5][6] Current research aims to further understand the biological mechanism underlying cardiomyocyte proliferation in hopes to turn this capability back on in adults in order to combat heart disease.

## By species

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### Zebrafish

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Adult zebrafish have a remarkable ability to completely regenerate cardiac muscle after injury.[7] There are similar genes in zebrafish and humans that control the development of the heart[8] and the phenomenal ability of zebrafish cardiomyocytes to proliferate in response to injury has made it a popular research model. When approximately 20% of the ventricle is resected from adult zebrafish, the cardiac muscle completely regenerates. Injury stimulates a subset of cardiomyocytes in the zebrafish heart that are able to proliferate and dedifferentiate.[9] Cardiomyocytes of zebrafish are mononucleated and diploid.[10]

### Mammals

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After cardiomyocyte proliferation and regeneration was demonstrated to occur in zebrafish after resection, various animal models were utilized in order to explore whether mammals also have this innate ability. In 2011, Porrello et al. demonstrated that neonatal mice are able to regenerate heart muscle after resection.[11] Since 2011, many other research groups have explored cardiomyocyte regeneration. The cardiomyocytes of neonatal rats[12] and piglets[13] are also able to undergo proliferation in response to injury during the first week of life.

### Humans

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In 2009, Dr. Jonas Frisén's research group used a technique implementing carbon-dating of cardiomyocytes to propose that human adult cardiomyocytes do proliferate, but at a very slow rate.[14] There have also been case reports that suggest that the cardiomyocytes of newborns are able to proliferate in response to ischemia.[15][16] A 2013 paper demonstrated that there are a small number of cardiomyocytes in mitosis and cytokinesis in humans up to age 20, with the highest percentage present in infants.[17]

## Signaling pathways

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The complete biological mechanism underlying cardiomyocyte proliferation has not been fully elucidated. However, there are various transcription factors and signaling cascades thought to be very important. Cardiomyocytes have been shown to be encouraged to exit the cell cycle then cyclin-dependent kinases are downregulated, or when cell cycle inhibitors are introduced.[18] Many of the signals that a cell receives during phase G1 determine whether the cell will undergo proliferation. Cyclin-dependent kinases and cyclin-dependent kinase inhibitors play key roles in this process.[19] One gene, jumonji (jmj), has been shown to start increasing in its expression in embryonic day 10.5 mice and is proposed to help cease the proliferation of cardiomyocytes by repressing the expression of cyclin D1.[20] Jumonji is believed to recruit G9a and GLP methyltransferases to the cyclin D1 promoter, which are thought to methylate histones H3-H9 and repress cyclin D1 expression.[21]

The transcription factor family E2F are also thought to be very important in regulating cardiomyocyte proliferation. E2F transcription factors influence cellular proliferation and help control apoptosis. When cardiomyocytes were transfected with adenoviruses expressing E2F2, cyclins A and E were upregulated, and cardiomyocytes proliferated.[22]

The cessation of the cardiomyocyte cell cycle is believed to be regulated by transcription factors and cyclin dependent kinase inhibitors, although the exact mechanism remains unclear.[23] One transcription facet that has been shown to be key in his process is Meis1.[24] Meis1 has been shown to be necessary for the activation of the cyclin-dependent kinase inhibitors p15, p16, and p21. Knockout experiments demonstrated that the length of cardiomyocyte proliferation can be extended when Meis1 is deleted in mice.[25] Meis1 has been shown to play a role in the regulation of anaerobic glycolysis.[26] This is particularly interesting because cardiomyocytes undergo a shift in their metabolism during development: cardiomyocytes rely on glycolytic metabolism but switch to relying on oxidative phosphorylation.[27] One research group demonstrated that neonatal transgenic mice deficient in fatty acids had a longer time span in which their cardiomyocytes were able proliferate in response to injury.[28]

Furthermore, oxygen metabolism is thought to play a role in cardiomyocyte proliferation. Using a mouse model of myocardial infarction to induce cardiac tissue damage, adult mice exhibited an increase in the proliferation of cardiomyocytes when put in a hypoxic environment.[29] When mice are born, they switch from being in a hypoxic intrauterine environment to an environment rich in oxygen. One research group has shown that oxidative DNA damage to cells and the cellular response to this damage increases in the first week of life, which correlates with the time point when mammalian cardiomyocytes start to lose the ability to regenerate.[30] In the intrauterine environment, cardiomyocytes have limited exposure to oxygen and little damage from reactive oxygen species. At the same time, cardiomyocytes are proliferating in utero. When neonatal mice were exposed to a hypoxic environment after ischemic heart damage, the cardiomyocytes are encouraged to enter mitosis and proliferate.[31]

Another signaling pathway thought to be important for the ability of cardiomyocytes to proliferate is the Hippo pathway, which was previously shown to regulate organ size in a fruit fly model.[32] When key proteins in the Hippo pathway are inactivated in a mouse model, the embryos exhibit cardiomyocyte proliferation and cardiomegaly. Hippo is thought to interact with the Wnt signaling pathway to limit the size of the heart and encourage cessation of cardiomyocyte proliferation.[33]

## Clinical implications

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Heart disease continues to be one of the leading causes of death in the United States.[34] The progression of coronary artery disease can lead to weakened heart muscle and heart failure. If atherosclerosis progresses to the point of occluding a coronary artery, myocardial ischemia and damage can occur, resulting in irreversible cardiomyocyte death.[35] Further understanding of the biological mechanism underlying the cardiomyocyte proliferation that has been demonstrated in adult zebrafish and neonatal mice, rats, and piglets could provide insight into how it may be possible to encourage cardiomyocyte proliferation and heart regeneration in patients with ischemic heart disease or for patients in heart failure.[36]

## References

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1. ^ Parmacek MS, Epstein JA (2005). "Pursuing cardiac progenitors: regeneration redux". Cell. 120 (3): 295–298. doi:10.1016/j.cell.2005.01.025. PMID 15707888.
2. ^ Yen TH, Wright NA (2006). "The gastrointestinal tract stem cell niche". Stem Cell Reviews. 2 (3): 203–212. doi:10.1007/s12015-006-0048-1. PMID 17625256. S2CID 26595081.
3. ^ Sadek H, Olson EN (2020). "Toward the goal of human heart regeneration". Cell Stem Cell. 26 (1): 7–16. doi:10.1016/j.stem.2019.12.004. PMC 7257208. PMID 31901252.
4. ^ Mollova M, Bersell K, Walsh S, Salva J, Das LT, Park SY, Kühn B (2013). "Cardiomyocyte proliferation contributes to heart growth in young humans". Proceedings of the National Academy of Sciences. 110 (4): 1446–1451. Bibcode:2013PNAS..110.1446M. doi:10.1073/pnas.1214608110. PMC 3557060. PMID 23302686.
5. ^ Porello ER, Mahmoud, AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA (2011). "Transient regenerative potential of the neonatal mouse heart". Science. 331 (6020): 1078–1080. Bibcode:2011Sci...331.1078P. doi:10.1126/science.1200708. PMC 3099478. PMID 21350179.
6. ^ Wang H, Paulsen MJ, Hironaka CE, Shin HS, Farry JM, Thakore AD, Woo YP (2020). "Natural heart regeneration in a neonatal rat myocardial infarction model". Cells. 9 (1): 229. doi:10.3390/cells9010229. PMC 7017245. PMID 31963369.
7. ^ Poss KD, Wilson LG, Keating MT (2002). "Heart regeneration in zebrafish". Science. 298 (5601): 2188–2190. Bibcode:2002Sci...298.2188P. doi:10.1126/science.1077857. PMID 12481136. S2CID 7878193.
8. ^ Matrone G, Tucker CS, Denvir MA (2017). "cardiomyocyte proliferation in zebrafish and mammals: lessons for human disease". Cellular and Molecular Life Sciences. 74 (8): 1367–1378. doi:10.1007/s00018-016-2404-x. PMC 5357290. PMID 27812722.
9. ^ Jopling C, Sleep E, Raya M, Marti M, Raya A, Belmonte JC (2010). "Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation". Nature. 464 (7288): 606–609. Bibcode:2010Natur.464..606J. doi:10.1038/nature08899. PMC 2846535. PMID 20336145.
10. ^ Matrone G, Tucker CS, Denvir MA (2017). "Cardiomyocyte proliferation in zebrafish and mammals: lessons for human disease". Cellular and Molecular Life Sciences. 74 (8): 1367–1378. doi:10.1007/s00018-016-2404-x. PMC 5357290. PMID 27812722.
11. ^ Porello ER, Mahmoud, AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA (2011). "Transient regenerative potential of the neonatal mouse heart". Science. 331 (6020): 1078–1080. Bibcode:2011Sci...331.1078P. doi:10.1126/science.1200708. PMC 3099478. PMID 21350179.
12. ^ Wang H, Paulsen MJ, Hironaka CE, Shin HS, Farry JM, Thakore AD, Woo YP (2020). "Natural heart regeneration in a neonatal rat myocardial infarction model". Cells. 9 (1): 229. doi:10.3390/cells9010229. PMC 7017245. PMID 31963369.
13. ^ Zhu W, Zhang E, Zhao M, Chong Z, Fan C, Tang Y, Zhang J (2018). "Regenerative potential of neonatal porcine hearts". Circulation. 138 (24): 2809–2816. doi:10.1161/CIRCULATIONAHA.118.034886. PMC 6301098. PMID 30030418.
14. ^ Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barndabe-Heider F, Walsh S, Frisen J (2009). "Evidence for cardiomyocyte renewal in humans". Science. 324 (5923): 98–102. Bibcode:2009Sci...324...98B. doi:10.1126/science.1164680. PMC 2991140. PMID 19342590.
15. ^ Ling Y, Bhushan S, Fan Q, Tang M (2016). "Midterm outcome after surgical correction of anomalous left coronary artery from the pulmonary artery". Journal of Cardiothoracic Surgery. 11 (1): 137. doi:10.1186/s13019-016-0535-7. PMC 5000500. PMID 27562655.
16. ^ Huddleston CB, Balzer DT, Mendeloff EN (2001). "Repair of anomalous left main coronary artery arising from the pulmonary artery in infants: long-term impact on the mitral valve". The Annals of Thoracic Surgery. 71 (6): 1985–1988. doi:10.1016/s0003-4975(01)02518-8. PMID 11426779.
17. ^ Mollova M, Bersell K, Walsh S, Salva J, Das LT, Park SY, Kuhn B (2013). "Cardiomyocyte proliferation contributes to heart growth in young humans". Proceedings of the National Academy of Sciences. 110 (4): 1446–1451. Bibcode:2013PNAS..110.1446M. doi:10.1073/pnas.1214608110. PMC 3557060. PMID 23302686.
18. ^ Pasumarthi KB, Field LJ (2002). "Cardiomyocyte cell cycle regulation". Circulation Research. 90 (10): 1044–1054. doi:10.1161/01.res.0000020201.44772.67. PMID 12039793.
19. ^ Toyoda M, Shirato H, Nakajima K, Kojima M, Takahashi M, Kubota M, Takeuchi T (2003). "jumonji downregulates cardiac cell proliferation by repressing cyclin D1 expression". Developmental Cell. 5 (1): 85–97. doi:10.1016/s1534-5807(03)00189-8. PMID 12852854.
20. ^ Toyoda M, Shirato H, Nakajima K, Kojima M, Takahashi M, Kubota M, Takeuchi T (2003). "jumonji downregulates cardiac cell proliferation by repressing cyclin D1 expression". Developmental Cell. 5 (1): 85–97. doi:10.1016/s1534-5807(03)00189-8. PMID 12852854.
21. ^ Shirato H, Ogawa S, Nakajima K, Inagawa M, Kojima M, Tachibana M, Takeuchi T (2009). "A jumonji (Jarid2) protein complex represses cyclin D1 expression by methylation of histone H3-K9". Journal of Biological Chemistry. 284 (2): 733–739. doi:10.1016/s1534-5807(03)00189-8. PMID 12852854.
22. ^ Ebelt H, Zhang Y, Kampke A, Xu J, Sclitt A, Buerke M, Braun T (2008). "E2F2 expression induces proliferation of terminally differentiated cardiomyocytes in vivo". Cardiovascular Research. 80 (2): 219–226. doi:10.1093/cvr/cvn194. PMID 18628254.
23. ^ Matrone G, Tucker CS, Denvir MA (2017). "cardiomyocyte proliferation in zebrafish and mammals: lessons for human disease". Cellular and Molecular Life Sciences. 74 (8): 1367–1378. doi:10.1007/s00018-016-2404-x. PMC 5357290. PMID 27812722.
24. ^ Mahmoud AI, Kocabas F, Muralidhar SA, Kimura W, Koura AS, Thet S, Porrello ER, Sadek HA (2013). "Meis1 regulates postnatal cardiomyocyte cell cycle arrest". Nature. 497 (7448): 249–253. Bibcode:2013Natur.497..249M. doi:10.1038/nature12054. PMC 4159712. PMID 23594737.
25. ^ Malandraki Miller S, Lopez CA, Al-Siddiqi H, Carr CA (2018). "Changing Metabolism in Differentiating Cardiac Progenitor Cells—Can Stem Cells Become Metabolically Flexible Cardiomyocytes?". Frontiers in Cardiovascular Medicine. 5: 119. doi:10.3389/fcvm.2018.00119. PMC 6157401. PMID 30283788.
26. ^ Malandraki Miller S, Lopez CA, Al-Siddiqi H, Carr CA (2018). "Changing Metabolism in Differentiating Cardiac Progenitor Cells—Can Stem Cells Become Metabolically Flexible Cardiomyocytes?". Frontiers in Cardiovascular Medicine. 5: 119. doi:10.3389/fcvm.2018.00119. PMC 6157401. PMID 30283788.
27. ^ Malandraki Miller S, Lopez CA, Al-Siddiqi H, Carr CA (2018). "Changing Metabolism in Differentiating Cardiac Progenitor Cells—Can Stem Cells Become Metabolically Flexible Cardiomyocytes?". Frontiers in Cardiovascular Medicine. 5: 119. doi:10.3389/fcvm.2018.00119. PMC 6157401. PMID 30283788.
28. ^ Cardoso AC, Lam NT, Salva JJ, Nakada Y, Pereiera AH, Elnwasany A, Menedez-Montes I, Ensley EL, Petric UB, Sharma G, Sherry AD, Malloy CR, Khemtony C, Kinter MT, Tan WL, Sadek HA (2020). "Mitochondrial substrate utilization regulates cardiomyocyte cell cycle progression". Nature Metabolism. 2 (2): 167–178. doi:10.1038/s42255-020-0169-x. PMC 7331943. PMID 32617517.
29. ^ Nakada Y, Canseco DC, Thet S, Abdisalaam S, Asaithamby A, Santos CX, Shah AM, Zhang H, Faber JE, Kinter MT, Sadek HA (2017). "Hypoxia induces heart regeneration in adult mice". Nature. 541 (7636): 222–227. Bibcode:2017Natur.541..222N. doi:10.1038/nature20173. PMID 27798600. S2CID 4448907.
30. ^ Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, Sadek HA (2014). "the oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response". Cell. 157 (3): 565–579. doi:10.1016/j.cell.2014.03.032. PMC 4104514. PMID 24766806.
31. ^ Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, Sadek HA (2014). "the oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response". Cell. 157 (3): 565–579. doi:10.1016/j.cell.2014.03.032. PMC 4104514. PMID 24766806.
32. ^ Conlon L, Raff M (1999). "size control in animal development". Cell. 96 (2): 235–244. doi:10.1016/s0092-8674(00)80563-2. PMID 9988218.
33. ^ Heallen T, Zhang M, Bonilla-Claudio M, Klysik E, Johnson RL, Martin JF (2011). "Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size". Science. 332 (6028): 458–461. Bibcode:2011Sci...332..458H. doi:10.1126/science.1199010. PMC 3133743. PMID 21512031.
34. ^ Nowbar AN, Gitto M, Howard JP, Francis DP, Al-Lamee R (2019). "mortality from ischemic heart disease". Circ Cardiovasc Qual Outcomes. 12 (6): e005375. doi:10.1161/CIRCOUTCOMES.118.005375. PMC 6613716. PMID 31163980.
35. ^ Ferrari R (2001). "Pathophysiological vs biochemical ischaemia: a key to transition from reversible to irreversible damage". European Heart Journal Supplements. 3: C2–C10. doi:10.1016/S1520-765X(01)90024-0.
36. ^ Lam NT, Sadek HA (2018). "Neonatal heart regeneration: comprehensive literature review". Circulation. 138 (4): 412–423. doi:10.1161/CIRCULATIONAHA.118.033648. PMC 6673675. PMID 30571359.